JPH06508352A - Use of tetrahydrobenzazepine derivatives for the treatment of portal hypertension and migraine - Google Patents
Use of tetrahydrobenzazepine derivatives for the treatment of portal hypertension and migraineInfo
- Publication number
- JPH06508352A JPH06508352A JP4511087A JP51108792A JPH06508352A JP H06508352 A JPH06508352 A JP H06508352A JP 4511087 A JP4511087 A JP 4511087A JP 51108792 A JP51108792 A JP 51108792A JP H06508352 A JPH06508352 A JP H06508352A
- Authority
- JP
- Japan
- Prior art keywords
- tetrahydro
- formula
- hydroxy
- benzazepine
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 208000019695 Migraine disease Diseases 0.000 title claims description 22
- 208000007232 portal hypertension Diseases 0.000 title claims description 22
- 206010027599 migraine Diseases 0.000 title claims description 19
- MZBVNYACSSGXID-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-1-benzazepine Chemical class N1CCCCC2=CC=CC=C21 MZBVNYACSSGXID-UHFFFAOYSA-N 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 15
- 239000000556 agonist Substances 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 150000002431 hydrogen Chemical group 0.000 claims description 12
- 102000005962 receptors Human genes 0.000 claims description 11
- 108020003175 receptors Proteins 0.000 claims description 11
- 239000000018 receptor agonist Substances 0.000 claims description 9
- 229940044601 receptor agonist Drugs 0.000 claims description 9
- 102000056834 5-HT2 Serotonin Receptors Human genes 0.000 claims description 7
- 108091005479 5-HT2 receptors Proteins 0.000 claims description 7
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 230000002265 prevention Effects 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- AHXWNPZRTBMBJW-UHFFFAOYSA-N 1-(7-hydroxy-2,3,4,5-tetrahydro-1h-1-benzazepin-8-yl)ethanone Chemical compound N1CCCCC2=C1C=C(C(=O)C)C(O)=C2 AHXWNPZRTBMBJW-UHFFFAOYSA-N 0.000 claims description 3
- UUAJXCLXKIGVEO-UHFFFAOYSA-N 8-(trifluoromethylsulfonyl)-2,3,4,5-tetrahydro-1h-1-benzazepin-7-ol Chemical compound C1CCCNC2=C1C=C(O)C(S(=O)(=O)C(F)(F)F)=C2 UUAJXCLXKIGVEO-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 229940126585 therapeutic drug Drugs 0.000 claims description 3
- YONPGGFAJWQGJC-UHFFFAOYSA-K titanium(iii) chloride Chemical compound Cl[Ti](Cl)Cl YONPGGFAJWQGJC-UHFFFAOYSA-K 0.000 claims description 3
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
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- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- WCYXJUWAKAVQPX-UHFFFAOYSA-N 8-methylsulfinyl-2,3,4,5-tetrahydro-1h-1-benzazepin-7-ol Chemical compound N1CCCCC2=C1C=C(S(=O)C)C(O)=C2 WCYXJUWAKAVQPX-UHFFFAOYSA-N 0.000 claims 1
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Abstract
(57)【要約】本公報は電子出願前の出願データであるため要約のデータは記録されません。 (57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.
Description
【発明の詳細な説明】 門脈圧冗進症および片頭痛の治療用のテトラヒドロベンズアゼピン誘導体の使用 本発明は、過度の血管拡張を特徴とする障害の治療、特に門脈圧冗進症の治療、 ならびに片頭痛の治療および予防において用いるためのある種のテトラヒドロベ ンズアゼピン誘導体に、さらに一般的には門脈圧冗進症の治療における５−ＨＴ 、および５−ＨＴ、様レセプターアゴニストの使用に、および片頭痛の治療およ び予防における５−ＨＴ、アゴニストの使用に関する。[Detailed description of the invention] Use of tetrahydrobenzazepine derivatives for the treatment of portal hypertension and migraine The present invention relates to the treatment of disorders characterized by excessive vasodilation, in particular the treatment of portal hypertension; and certain tetrahydrobenzenes for use in migraine treatment and prevention. 5-HT in the treatment of portal hypertension, and more generally in the treatment of portal hypertension. , and for the use of 5-HT, like receptor agonists, and for the treatment of migraine and 5-HT, the use of agonists in the prevention and prevention of 5-HT.
通常、肝硬変に付随する門脈圧冗進症は、（腸間膜細動脈の拡張に起因する）門 脈系静脈血流の増加、および門脈系血管抵抗の増加によって特徴付けられる。Portal hypertension (due to dilatation of mesenteric arterioles), which usually accompanies liver cirrhosis, It is characterized by increased venous blood flow and increased portal vascular resistance.
この症状の重度の合併症は、食道静脈瘤または傍食道側副枝（ｐａｒａｅｓｏｐ ｈａｇｅａｌｃｏｌｌａｔｅｒａｌ）の破裂であり、それは門脈圧の低下へと発 展する。Severe complications of this condition include esophageal varices or paraesophageal collaterals. rupture of the hagealcollateral), which leads to a drop in portal pressure. Exhibit.
今回、胃腸運動障害の治療薬としてその分野において公知のある種のテトラヒド ロベンズアゼピンが、５−ＨＴ、および／または５−ＨＴ、様レセプターでのア ゴニストであることが見いだされ、門脈圧冗進症の治療において有用性があると 考えられる。This time, we will discuss certain types of tetrahydrides known in the field as therapeutic agents for gastrointestinal motility disorders. Robenzazepine's activity at 5-HT and/or 5-HT-like receptors agonist and may be useful in the treatment of portal hypertension. Conceivable.
片頭痛は、１０人に１人が患っている非致命性疾患である。主たる徴候は頭痛で あり、別には嘔吐および羞明症を包含する。現在、片頭痛の治療に最も広範に用 いられているものとして、エルゴタミン、ジヒドロエルゴタミンまたはメチセル シトの投与が挙げられる。これら薬剤はすべて、とりわけ、５−ＨＴＩ様レセプ ターのアゴニストであるが、他の作用も有しており、それらの薬剤での治療には 多くの副作用を伴う。加えて、ある患者は、エルゴタミンのような変角製品を用 いる治療を中止した後に「禁断性頭痛」を経験しており、そのため、その治療が 繰り返し行われ、その結果、嗜癖が形成されることとなる。Migraine is a non-fatal disease that affects one in ten people. The main symptom is a headache Other symptoms include vomiting and photophobia. Currently the most widely used treatment for migraine headaches. Ergotamine, dihydroergotamine or methycel as used For example, administration of cito. All of these drugs have inter alia 5-HTI-like receptors. agonist, but also has other effects, and treatment with these drugs With many side effects. In addition, some patients use morphing products such as ergotamine. I am experiencing a "withdrawal headache" after discontinuing a treatment that I am currently taking, which makes it difficult for me to stop using that treatment. This is done repeatedly, and as a result, an addiction is formed.
したがって、片頭痛の治療について効果的かつ安全な薬剤の提供に対する要求が あることは明らかである。Therefore, there is a need for the provision of effective and safe drugs for the treatment of migraine. It is clear that there is.
今回、胃腸運動障害の治療の分野において知られているある種のテトラヒドロベ ンズアゼピンが、５−ＨＴ、様および／または５−ＨＴ２レセプターでのアゴニ ストであることが見いだされ、片頭痛の治療において有用性があると考えられる 。This time, we will discuss a certain type of tetrahydrobenzene known in the field of treatment of gastrointestinal motility disorders. agonism at 5-HT, like and/or 5-HT2 receptors. It has been found that this drug is effective in treating migraines and may be useful in treating migraines. .
したがって、本発明は、門脈圧冗進症および／または片頭痛の治療薬の製造にお いて用いるための式（Ｉ）゛ １式中、 Ｒは水素、Ｃｌ−６アルキルまたはＣ５−５アルケニル；Ｒ１はＮｏ！、シアノ 、ハロ、ＣＯＲ”、ＳＯ，Ｒ’またはＳＯいＮＲ５Ｒ６゜Ｒ２は水素、ヒドロキ シまたはＣ，，４アルコキシ：Ｒ３は水素、Ｃ１−４アルキル、ＯＲ１またはＮ Ｒ８Ｒ＠：Ｒ４はＣ１，６アルキルまたはハロＣ７−６アルキル；Ｒ５およびＲ ｅは水素、Ｃｌ−６アルキルまたはＣ！−６シクロアルキル；およびｎは１また は２を意味する］ で示される化合物およびその医薬上許容される塩を提供する。Therefore, the present invention is applicable to the production of a therapeutic drug for portal hypertension and/or migraine. Formula (I) for use in In one set, R is hydrogen, Cl-6 alkyl or C5-5 alkenyl; R1 is No! , cyano , halo, COR”, SO, R’ or SONR5R6°R2 is hydrogen, hydroxy C or C,,4 alkoxy: R3 is hydrogen, C1-4 alkyl, OR1 or N R8R@: R4 is C1,6 alkyl or haloC7-6 alkyl; R5 and R e is hydrogen, Cl-6 alkyl or C! -6 cycloalkyl; and n is 1 or means 2] Provided are compounds represented by and pharmaceutically acceptable salts thereof.
適当には、Ｒは水素、Ｃｌ−６アルキルまたはＣ３−５アルケニルであり、好ま しくはＲは水素である。Suitably R is hydrogen, Cl-6 alkyl or C3-5 alkenyl, preferably Alternatively, R is hydrogen.
適当には、Ｒ１はニトロ、シアノ、ハロ、ＣＯＲ３、Ｓｏ、Ｒ’またはＳｏ、Ｎ Ｒ５Ｒ６てあり、好ましくはＲ１はＳＯ，Ｒ’、ニトロまたはハロであり、最も 好ましくはＲ１はＳｏ、Ｒ’である。Suitably R1 is nitro, cyano, halo, COR3, So, R' or So, N R5R6, preferably R1 is SO, R', nitro or halo, most Preferably R1 is So, R'.
適当にはｎは１または２であり、好ましくはｎは２である。Suitably n is 1 or 2, preferably n is 2.
適当にはＲ２は水素、ヒドロキシまたはＣｌ−１アルコキシであり、好ましくは Ｒ２はＣｌ−４アルコキシまたはヒドロキシである。Suitably R2 is hydrogen, hydroxy or Cl-1 alkoxy, preferably R2 is Cl-4 alkoxy or hydroxy.
適当にはＲ３は水素、Ｃ１−４アルキル、αＰまたはＮＲ’Ｒ”であり、好まし くはＲ３はＣ１−４アルキル、特にメチルである。Suitably R3 is hydrogen, C1-4 alkyl, αP or NR'R'', preferably or R3 is C1-4 alkyl, especially methyl.
好ましくはＲ１基は、式（Ｉ）の化合物の環の８−位にあり、Ｒ１基は７−位に ある。Preferably the R1 group is in the 8-position of the ring of the compound of formula (I) and the R1 group is in the 7-position. be.
適当にはＲ４はＣｌ−ｓアルキルまたはハロＣ１−、アルキルである。好ましく はＲ４はＣｌ−Ｓアルキルまたは１〜６個のハロゲン原子で置換されたＣ５−。Suitably R4 is Cl-s alkyl or haloC1-,alkyl. preferably R4 is Cl-S alkyl or C5- substituted with 1 to 6 halogen atoms.
アルキル（例えば、ＣＦりであり、最も好ましくはＲ４はメチルである。Alkyl (eg, CF, most preferably R4 is methyl).
適当にはＲ５およびＲ６は水素またはＣ１−、アルキル、またはｃ、−６シクロ アルキルである。両方の基がＣｌ−Ｓアルキルである場合、それらは同一である ことが好ましい。Suitably R5 and R6 are hydrogen or C1-, alkyl, or c,-6cyclo It is an alkyl. If both groups are Cl-S alkyl, they are the same It is preferable.
単独または別の基の一部であるいずれかの自−６アルキル基は、直鎖または分枝 鎖とすることができる。Any auto-6 alkyl group, alone or as part of another group, may be straight-chain or branched. It can be a chain.
適当な塩は当業者にとって明らかであり、例えば、塩酸塩またはシュウ酸塩のよ うな酸付加塩を包含する。Suitable salts will be apparent to those skilled in the art, such as, for example, the hydrochloride or oxalate. Includes uric acid addition salts.
本発明の使用のための化合物の適当な例は、ＥＰ−０２２９５１０−Ｈに記載さ れているような、例えばニ ツーヒドロキシ−８−スルファモイル−２，３，４，５−テトラヒドロ−１）（ −ベンズアゼピン、および ７−ヒドロキシ−８−（Ｎ、 Ｎ−ジメチルスルファモイル）−２，３，４，５ −テトラヒドロ−ＩＨ−ベンズアゼピンである。Suitable examples of compounds for use in the present invention are described in EP-0229510-H. For example, dihydroxy-8-sulfamoyl-2,3,4,5-tetrahydro-1) ( - benzazepine, and 7-hydroxy-8-(N, N-dimethylsulfamoyl)-2,3,4,5 -tetrahydro-IH-benzazepine.
特に、本発明は、片頭痛の治療薬の製造における、Ｒが水素、Ｒ１がメチルスル ホニルであって、Ｒ２がヒドロキシである化合物、すなわち、７−ヒドロキシ− ８−メチルスルホニル−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン またはその医薬上許容される塩の使用に関する。In particular, the present invention provides a method for producing a therapeutic drug for migraine, in which R is hydrogen and R1 is methyl sulfur. Compounds in which R2 is hydroxy, i.e. 7-hydroxy- 8-Methylsulfonyl-2,3,4,5-tetrahydro-IH-benzazepine or the use of a pharmaceutically acceptable salt thereof.
式（１）の範囲内に含まれるある種の化合物はそれ自体が新規であって、それが 本発明のさらなる態様を形成する。これらの化合物は、特に。Certain compounds falling within the scope of formula (1) are novel in themselves; Forms a further aspect of the invention. These compounds especially.
７−メドキシー８−メチルスルフィニル−２，３，４，５−テトラヒドロ−ＩＨ −ベンズアゼピン・シュウ酸塩ニ ツーメトキシ−８−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩； ７−ヒドロキシ−８−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズア ゼピン・塩酸塩； ７−メドキシー８−ブロモ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩。7-medoxy8-methylsulfinyl-2,3,4,5-tetrahydro-IH -Benzazepine oxalate Twomethoxy-8-nitro-2,3,4,5-tetrahydro-IH-benzaze Pin hydrochloride; 7-Hydroxy-8-nitro-2,3,4,5-tetrahydro-IH-benza Zepine hydrochloride; 7-medoxy 8-bromo-2,3,4,5-tetrahydro-IH-benzaze Pin hydrochloride.
７−ヒドロキシ−８−ブロモ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズア ゼピン・塩酸塩； ７−メドキシー６−ニトロー２．３．４．５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩。7-hydroxy-8-bromo-2,3,4,5-tetrahydro-IH-benza Zepine hydrochloride; 7-medoxy 6-nitro 2.3.4.5-tetrahydro-IH-benzaze Pin hydrochloride.
６−プロモーフ−メトキシー２．３．４．５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩； ８−アセチル−７−ヒドロキシ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズ アゼピン・塩酸塩ニ マーヒドロキシ−８−メチルスルフィニル−２，３，４，５−テトラヒドロ−Ｉ Ｈ−ベンズアゼピン、および ７−ヒドロキシ−８−トリフルオロメチルスルホニル−２，３，４，５−テトラ ヒドロ−ＩＨ−ベンズアゼピンである。6-promorph-methoxy2.3.4.5-tetrahydro-IH-benzaze Pin hydrochloride; 8-acetyl-7-hydroxy-2,3,4,5-tetrahydro-IH-benz Azepine/hydrochloride merhydroxy-8-methylsulfinyl-2,3,4,5-tetrahydro-I H-benzazepine, and 7-hydroxy-8-trifluoromethylsulfonyl-2,3,4,5-tetra Hydro-IH-benzazepine.
式（１）の化合物は、ＥＰ−０２２９５１０−Ｂに記載の方法により製造しても よく、または以下の方法により製造してもよい：ａ）式（Ｉ）の化合物（式中、 Ｒ１は一３Ｏ，Ｒ’を示す）を製造するのに、式（ＩＩ）・ ［式中、Ｒ１およびＲ４は前記と同じであり、Ｒ７はＮ−保護基を意味する］で 示される化合物を、三塩化チタンの存在下、酸化剤と反応させ；ｂ）式（Ｉ）の 化合物（式中、Ｒ１は−ＣＯＲ３、ＮＯｘまたはハロゲンを示す）を製造するの に、式（Ｉ［［） ［式中、Ｒ２、Ｒ３およびＲ７は前記と同じ〕で示される化合物を、各々、適当 なアシル化剤、ニトロ化剤またはハロゲン化剤と反応させ、つづいて各ケースに おいてＮ−保護基を除去し、所望により塩を形成させる。The compound of formula (1) can also be produced by the method described in EP-0229510-B. or may be prepared by: a) a compound of formula (I) in which: R1 represents -3O,R'), the formula (II) [wherein R1 and R4 are the same as above, and R7 means an N-protecting group] reacting the indicated compound with an oxidizing agent in the presence of titanium trichloride; b) of formula (I); For producing a compound (wherein R1 represents -COR3, NOx or halogen) , the formula (I[[) [In the formula, R2, R3 and R7 are the same as above] respectively, as appropriate. acylating, nitrating or halogenating agents, followed by in each case The N-protecting group is removed and a salt is formed if desired.
適当なＮ−保護基Ｒ７はその分野において周知であり、アセチル、トリフルオロ アセチル、ベンゾイル、メトキシカルボニルおよびベンジルオキシカルボニルの ようなアシル基を包含する。Ｎ−脱保護は常法にて行うことができる。Suitable N-protecting groups R7 are well known in the art and include acetyl, trifluoro Acetyl, benzoyl, methoxycarbonyl and benzyloxycarbonyl It includes acyl groups such as N-deprotection can be carried out by conventional methods.
方法（ａ）において、酸化剤は、例えば、酢酸のような溶媒中、過酸化水素また は３−クロロ過安息香酸のような過酸とすることができる。１当量の酸化剤で、 ｎが１である化合物を生成し、２またはそれ以上の当量でｎが２である化合物を 得ることが認識されるであろう。In method (a), the oxidizing agent is, for example, hydrogen peroxide or can be a peracid such as 3-chloroperbenzoic acid. With 1 equivalent of oxidizing agent, to produce compounds where n is 1, and in equivalents of 2 or more to produce compounds where n is 2. Gains will be recognized.
方法（ｂ）において、アシル化剤は、Ｒ”ＣＯ−基に対応する酸塩化物または酸 無水物であってもよい。反応は、四塩化スズの存在下で行うことが望ましい。In method (b), the acylating agent is an acid chloride or an acid corresponding to the R''CO- group. It may be anhydrous. The reaction is preferably carried out in the presence of tin tetrachloride.
ニトロ化は、無水酢酸との混合物中、濃硝酸を用いて行い、つづいて例えば、炭 酸水素ナトリウムで中和してもよい。ハロゲン化は、ハロゲンの酸性溶液、例え ばＢｒ２の酢酸溶液を用いて行い、つづいて例えば、炭酸水素ナトリウムで中和 してもよい。一般に、ニトロ化およびハロゲン化反応は、ベンズアゼピン環の７ ゜８および６．７位が、各々、置換している異性体の混合物をもたらし、それは 、例えば、クロマトグラフィーまたは結晶化操作により分離できる。Nitration is carried out using concentrated nitric acid in a mixture with acetic anhydride, followed by e.g. It may be neutralized with sodium hydroxide. Halogenation is an acidic solution of a halogen, e.g. For example, using an acetic acid solution of Br2, followed by neutralization with, for example, sodium hydrogen carbonate. You may. Generally, nitration and halogenation reactions are carried out at the 7 The 8 and 6.7 positions each result in a mixture of isomers being substituted, which is , for example, by chromatography or crystallization operations.
式（Ｉ）の化合物は、５−ＨＴ、および／または５−ＨＴ、様レセプターについ てのアゴニストであることが判明し、門脈圧冗進症の治療または予防における医 薬にて有用性を有すると考えられる。理論的にはともあれ、５−ＨＴ、様アゴニ ストおよび５− ＨＴ ２アゴニストは、腸間膜動脈を収縮させ、および傍食道 側副枝を部分的に収縮させ、その結果、門脈血流および門脈圧を低下させること により門脈圧冗進症に効果的であると考えられる。本発明に係る使用について好 ましい化合物は、５−ＨＴ２レセプターおよび／または５−ＨＴ、様レセプター での部分的アゴニストである。Compounds of formula (I) are suitable for 5-HT and/or 5-HT, like receptors. agonist in the treatment or prevention of portal hypertension. It is thought to have usefulness in medicine. Theoretically speaking, 5-HT, similar agony ST and 5-HT2 agonists constrict mesenteric arteries and paraesophageal Partially constricting collaterals, thereby reducing portal blood flow and portal pressure It is considered to be effective for portal hypertension. Preferred for use in accordance with the present invention Preferred compounds are 5-HT2 receptors and/or 5-HT, like receptors. It is a partial agonist.
門脈圧冗進症の治療における５−ＨＴＩおよび５−ＨＴ、様レセプターアゴニス トの使用は今までに記載されておらず、かくしてこれら一連の化合物についての 新規用途を表すものと考えられる。したがって、さらなる態様において、本発明 は、門脈圧冗進症の治療において用いるための５−ＨＴ、レセプターアゴニスト および５−ＨＴ、様アゴニストを提供する。本発明はまた、門脈圧冗進症の治療 薬の製造における５−ＨＴ２レセプターアゴニストおよび５−ＨＴ、様アゴニス トの使用を提供する。さらに、本発明は有効量の５−ＨＴ２アゴニストまたは５ −ＨＴ ＋ 様アゴニストを門脈圧光進症の治療を必要とする対象に投与するこ とからなる門脈圧冗進症の治療法を提供する。本発明に係る使用では、５−ＨＴ ２アゴニストまたは５−ＨＴ ｆ様アゴニストは、該レセプターでの部分的アゴ ニストであることが好ましい。最も好ましくは、本発明に係る使用の場合、化合 物は５−ＨＴ２および５−ＨＴ、様の両方のレセプターでの部分的アゴニストで ある。5-HTI and 5-HT, like receptor agonism in the treatment of portal hypertension The use of these compounds has not been previously described and thus It is thought that it represents a new use. Therefore, in a further aspect, the present invention 5-HT, a receptor agonist for use in the treatment of portal hypertension and 5-HT, like agonists. The present invention also provides treatment for portal hypertension. 5-HT2 receptor agonists and 5-HT, like agonists in the manufacture of drugs provide the use of Additionally, the present invention provides effective amounts of 5-HT2 agonists or 5-HT2 agonists. - Administering HT+-like agonists to subjects in need of treatment for portal hypertension. To provide a treatment method for portal hypertension consisting of. In the use according to the invention, 5-HT 2 agonists or 5-HT f-like agonists are partial agonists at the receptor. Preferably, it is a list. Most preferably, for use according to the invention, the compound is a partial agonist at both 5-HT2 and 5-HT-like receptors. be.
式（Ｉ）の化合物が、５−ＨＴＩ様および／または５−ＨＴ！レセプターでのア ゴニストであることが見いだされ、片頭痛の治療または予防における医薬にて有 用性を有すると考えられる。理論的にはともあれ、５−ＨＴＩ様アゴニストが大 脳動脈の収縮を介して片頭痛に効果的であり、５−ＨＴ、アゴニストが浅側頭動 脈を収縮すると考えられる。本発明に係る使用のための好ましい化合物は、５− ＨＴ、様および／または５−ＨＴ２レセプターでの部分的アゴニストである。The compound of formula (I) is 5-HTI-like and/or 5-HT! receptor has been found to be a migraine agonist and has value in medicine in the treatment or prevention of migraine. It is thought that it has utility. Theoretically speaking, 5-HTI-like agonists are It is effective for migraine through constriction of cerebral arteries, and 5-HT and agonists stimulate superficial temporal movement. It is thought to constrict the pulse. Preferred compounds for use according to the invention are 5- It is a partial agonist at the HT-like and/or 5-HT2 receptors.
片頭痛の治療における５−ＨＴ、レセプターアゴニストの使用は今までに記載さ れておらず、かくしてこの種の化合物についての新規用途を表すものと考えられ る。したがって、さらなる態様において、本発明は、片頭痛の治療において用い るための５−ＨＴ２レセプターアゴニストを提供する。本発明はまた、片頭痛の 治療薬の製造における５−ＨＴｓレセプターアゴニストの使用を提供する。さら に、本発明は有効量の５−ＨＴ、アゴニストを片頭痛の治療を必要とする対象に 投与することからなる片頭痛の治療法を提供する。本発明に係る使用では、５− ＨＴ２アゴニストは、好ましくは、このレセプターでの部分的アゴニストである 。The use of 5-HT, receptor agonists in the treatment of migraine has not been previously described. has not been proposed and is thus considered to represent a new use for this type of compound. Ru. Accordingly, in a further aspect, the present invention provides for use in the treatment of migraine. 5-HT2 receptor agonists are provided. The present invention also provides treatment for migraine Provided is the use of a 5-HTs receptor agonist in the manufacture of a therapeutic agent. Sara In addition, the present invention provides an effective amount of 5-HT, an agonist to a subject in need of treatment for migraine. Provided is a method of treating migraine comprising administering a migraine. In the use according to the invention, 5- The HT2 agonist is preferably a partial agonist at this receptor .
治療的使用において、該化合物を標準医薬組成物中に配合する。該組成物は経口 的、非経口的、直腸的または経皮的に投与できる。In therapeutic use, the compounds are incorporated into standard pharmaceutical compositions. The composition can be administered orally. It can be administered subcutaneously, parenterally, rectally or transdermally.
経口投与した場合に活性である式（Ｉ）の化合物およびその医薬上許容される塩 は、液体、例えば、シロップ、懸濁液またはエマルジョン、錠剤、カプセルおよ びロゼンジとして処方できる。Compounds of formula (I) and pharmaceutically acceptable salts thereof that are active when administered orally liquids, such as syrups, suspensions or emulsions, tablets, capsules and It can be prescribed as a lozenge.
液体処方は、一般に、適当な液体担体中、例えば、エタノール、グリセリン、非 水性溶媒、例えばポリエチレングリコール、油類または水中、該化合物または医 薬上許容される塩の懸濁液または溶液と、沈殿防止剤、保存剤、フレーバー剤ま たは着色剤とからなる。Liquid formulations are generally prepared in a suitable liquid carrier, such as ethanol, glycerin, non- in aqueous solvents such as polyethylene glycols, oils or water, Suspensions or solutions of pharmaceutically acceptable salts with suspending agents, preservatives, flavoring agents or or a coloring agent.
錠剤形の組成物は、固体処方の製造に慣用的に用いられるいずれの適当な医薬担 体を用いることによっても製造できる。このような担体は、例えばステアリン酸 マグネシウム、澱粉、ラクトース、シュークロースおよびセルロースを包含する 。Compositions in tablet form may be prepared using any suitable pharmaceutical carrier conventionally used in the manufacture of solid formulations. It can also be produced using the human body. Such carriers include, for example, stearic acid. Contains magnesium, starch, lactose, sucrose and cellulose .
カプセル形の組成物は慣用のカプセル化操作を用いて製造できる。例えば、活性 成分含有のペレットを標準担体を用いて製造し、ついでノ１−ドゼラチンカプセ ル中に充填する；別法として、分散液または懸濁液をいずれか適当な医薬担体、 例えば水性ガム、セルロース、シリケートまたは油類を用いて製造し、ついで該 分散液または懸濁液をソフトゼラチンカプセル中に充填する。Compositions in capsule form can be manufactured using conventional encapsulation procedures. For example, active Pellets containing the ingredients are prepared using standard carriers and then added to gelatin capsules. Alternatively, the dispersion or suspension can be filled into a suitable pharmaceutical carrier; For example, it is produced using water-based gums, cellulose, silicates or oils, and then the The dispersion or suspension is filled into soft gelatin capsules.
非経口的に（すなわち、注射または点滴により）投与した場合に活性である式（ Ｉ）の化合物は、溶液または懸濁液として処方できる。Formulas that are active when administered parenterally (i.e. by injection or infusion) ( The compounds of I) can be formulated as solutions or suspensions.
非経口投与用の組成物は、一般に、滅菌水性担体または非経口的に許容される油 、例えばポリエチレングリコール、ポリビニルピロリドン、レシチン、落花生油 またはゴマ油中、活性成分の溶液または懸濁液からなる。別法として、該溶液を 凍結乾燥し、ついで投与直前に適当な溶媒で復元できる。Compositions for parenteral administration generally include a sterile aqueous carrier or a parenterally acceptable oil. , such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or consisting of a solution or suspension of the active ingredient in sesame oil. Alternatively, the solution It can be lyophilized and then reconstituted with a suitable solvent immediately before administration.
典型的な坐剤組成物は、この方法にて投与した場合に活性である式（Ｉ）の化合 物またはその医薬上許容される塩と、結合剤および／または滑沢剤、例えばポリ マーグリコール、ゼラチンまたはココア脂または他の低融点植物または合成油脂 とからなる。A typical suppository composition will contain a compound of formula (I) that is active when administered in this manner. or a pharmaceutically acceptable salt thereof, a binder and/or a lubricant, such as a polyester. Marglycol, gelatin or cocoa butter or other low melting vegetable or synthetic oils It consists of
典型的な経皮処方は、慣用の水性または非水性ビヒクル、例えば、クリーム、軟 膏、ローションあるいはペーストまたは薬用プラスター、バッチあるいは膜の形 管からなる。Typical transdermal formulations include conventional aqueous or non-aqueous vehicles, e.g. creams, soft In the form of salves, lotions or pastes or medicinal plasters, batches or films Consists of tubes.
好ましくは、該組成物は単位投与形である。経口投与用の各用量単位は、好まし くは、１〜２５０ｍｇの式（Ｉ）の化合物または遊離塩基として換算したその医 薬上許容される塩を含有する（非経口投与の場合、好ましくは、０．１〜１５０ ｍｇを含有する）。Preferably, the composition is in unit dosage form. Each dosage unit for oral administration preferably contains or 1 to 250 mg of a compound of formula (I) or its pharmaceutical compound, calculated as free base. Contains a pharmaceutically acceptable salt (for parenteral administration, preferably 0.1 to 150 mg).
成人患者についての一日の投与計画は、例えば、式（Ｉ）の化合物または遊離塩 基として換算したその医薬上許容される塩が、経口投与では１ｍｇ〜１０００ｍ ｇ、好ましくは１ｍｇ〜４００ｍｇ、例えば１０ｍｇ〜４００ｍｇであり、静脈 内、皮下または筋肉内投与ではＯ，１ｍｇ〜１００ｍｇ、好ましくは０．１ｍｇ 〜３０ｍｇ、例えば１ｍｇ〜３０ｍｇであって、該化合物を一日に１〜４回投与 する。適当には、該化合物を連続的療法期間中投与する。A daily dosing regimen for adult patients may include, for example, a compound of formula (I) or the free salt The pharmaceutically acceptable salt thereof, calculated as a base, may be administered in an amount of 1 mg to 1000 m g, preferably 1 mg to 400 mg, such as 10 mg to 400 mg, intravenously For intravenous, subcutaneous or intramuscular administration, O, 1 mg to 100 mg, preferably 0.1 mg. ~30 mg, such as 1 mg to 30 mg, administering the compound 1 to 4 times a day. do. Suitably, the compound is administered during a continuous therapy period.
生物学的データ ５−ＨＴ、様レセプタースクリーン イヌ伏在静脈 イヌ伏在静脈の螺旋体を、３７℃にて１０ｍＮの静止力で修飾クレブス溶液中に 固定した。該溶液はさらに、各々、１マイクロモル／リットルのケタンセリンブ ラゾシン、アトロピンおよびメピラミン、６マイクロモル／リットルのコカイン および２００マイクロモル／リットルのアスコルビン酸塩を含有した。略等尺性 の収縮を、ポリグラフ上、応力変換器で測定した。組織を２マイクロモル／リッ トルの５−ヒドロキシトリプタミン（５−ＨＴ）に２回暴露し、つづいて洗浄し た。試験化合物に対する累積濃度−効果曲線を測定し、つづいて使用した最高濃 度の試験化合物の存在下、５−ＨＴに対する曲線を測定した。試験化合物に起因 する収縮を、５−ＨＴに起因する収縮と比較した。試験化合物についての内在的 活性を２マイクロモル／リットルの５−ＨＴに起因する効果に対する試験化合物 誘発の効果の最大の割合として算定した。試験化合物のＥＣ，。を対応する作用 曲線より評価した。適当な平衡解離定数Ｋｐを、マラノおよびカラマン法（Ｍａ ｒａｎ。biological data 5-HT, like receptor screen canine saphenous vein The canine saphenous vein spiral was placed in modified Krebs solution at 37°C with a resting force of 10 mN. Fixed. The solution further contains 1 micromol/liter of ketanserin, respectively. lazosine, atropine and mepyramine, 6 micromoles/liter cocaine and 200 micromoles/liter of ascorbate. Approximately isometric The shrinkage was measured polygraphically with a stress transducer. tissue at 2 micromol/liter. Two exposures to 5-hydroxytryptamine (5-HT) followed by washing. Ta. A cumulative concentration-effect curve for the test compound was determined, followed by the highest concentration used. Curves for 5-HT were measured in the presence of 500% of the test compound. due to test compound The contraction caused by 5-HT was compared to that caused by 5-HT. Intrinsic for test compound Test compound on the effect due to 5-HT at 2 micromoles/liter of activity It was calculated as the maximum percentage of the effect of the induction. EC of test compound. The corresponding action Evaluation was made based on the curve. A suitable equilibrium dissociation constant Kp is determined using the Marano and Karaman method (Ma Ran.
＆Ｋａｕｍａｎｎ）より評価した（１９７６、ジャーナル・オン・ファーマコロ ジー・アンド・エクスペリメンタル・セラビューティックス（Ｊ、Ｐｈａｒｍａ ｃｏｌ、 Ｅｘｐ、 Ｔｈｅｒ、 ）よ１旦、５１８−５２５）。&Kaumann) (1976, Journal on Pharmacolo. G & Experimental Therapeutics (J, Pharma col, Exp, Ther, )yo1dan, 518-525).
式（Ｉ）の化合物は、このスクリーン法にて活性であることが証明され、例えば 、７−ヒドロキシ−８−メチルスルホニル−２，３，４，５−テトラヒドロ−Ｉ Ｈ−ベンズアゼピン（ＥＰ ２２９５１０−Ｂに記載の操作に従って製造）は、 ０．２μＭのＥＣ，。を有し、実施例１の化合物は２０μＭのＥＣ，。を有する ことが判明した。Compounds of formula (I) have been shown to be active in this screen method, e.g. , 7-hydroxy-8-methylsulfonyl-2,3,4,5-tetrahydro-I H-benzazepine (manufactured according to the procedure described in EP 229510-B) EC of 0.2 μM. and the compound of Example 1 had an EC of 20 μM. have It has been found.
ウサギ脳底動脈 方法 既に記載の方法に類似する方法にて、ウサギより単離した脳底動脈の頭蓋内勤層 にて実験を行った（パーソンズおよびウォーレイ（ｐＢｒｓｏｎｓおよびＷｈａ ｌｌｅｙ） 。rabbit basilar artery Method Intracranial layer of basilar artery isolated from rabbit by a method similar to that previously described. (Parsons and Wha) lley).
１９８９、ヨーロピアン・ジャーナル０オブ・ファーマコロジー（Ｅｕｒ、 Ｊ 、 Ｐｈａｒｍａｃｏｔ、）１７４，１８９−１９６）。1989, European Journal of Pharmacology (Eur, J , Pharmacot, ) 174, 189-196).
簡単には、ウサギを過量の麻酔薬（ベンドパルビトンナトリウム）により殺した 。脳全体を迅速に摘出し、水冷修飾クレブス溶液に浸漬し、脳底動脈を切開用顕 微鏡を用いて摘出した。クレブス溶液は、９５％０２１５％ＣＯ２で平衡にある 、以下の組成（ｍＭ）Ｎａ” （１２０）；Ｋ” （５）；Ｃａ” （２，２５ ）；Ｍｇ”（０゜５）；Ｃ１−（９８，５）； ＳＯ４２−（１）： ＥＤＴＡ （０，０４）からなる。内腔を細い金属ワイヤーで軽く擦ることにより内皮を 除去した。ついで、動脈を環セグメント（約４−５ｍｍ幅）に切断し、Ｎａ” （２０）；フマル酸塩（１０）；ピルビン酸塩（５）：Ｌ−グルタミン酸塩（５ ）およびグルコース（１０）を付加的に補足した修飾クレブス溶液（ｍＭ）の組 織名５０ｍ１中、等張圧を記録するために設置した。ついで、動脈を３−４ｍＮ の静止力の下に置き、３７℃に維持し、溶液を９５％０２１５％Ｃ０２で通気し た。Briefly, rabbits were killed with an overdose of anesthetic (bendoparbitone sodium). . The entire brain was quickly removed, immersed in water-cooled modified Krebs solution, and the basilar artery was placed under a dissection microscope. It was removed using a microscope. Krebs solution is in equilibrium at 95% 0215% CO2 , the following composition (mM) Na'' (120); K'' (5); Ca'' (2,25 ); Mg” (0°5); C1-(98,5); SO42-(1): EDTA Consists of (0,04). The endothelium is removed by gently rubbing the lumen with a thin metal wire. Removed. The artery was then cut into ring segments (approximately 4-5 mm wide) and (20); fumarate (10); pyruvate (5): L-glutamate (5 ) and modified Krebs solution (mM) additionally supplemented with glucose (10). It was installed to record isotonic pressure in a 50m1 room. Then, apply 3-4 mN to the artery. The solution was kept under static force at 37 °C and aerated with 95% CO2. Ta.
９０ｍＭのＫＣ１脱分極性溶液との初期反応性および５−ＨＴ （１０ｍＭ）予 備収縮のアセチルコリン誘発の弛緩の欠如を試験した後、５−ＨＴに対する累積 濃度−作用曲線（２ｎＭ−６０ｍＭ）を、アスコルビン酸塩２００ｍＭ、コカイ ン６ｍＭ、インドメタシン２．８ｍＭ、チタンセリン１ｍＭおよびプラゾシン１ ｍＭの存在下で作成した。Initial reactivity with 90mM KC1 depolarizing solution and 5-HT (10mM) pre- Cumulative response to 5-HT after testing for lack of acetylcholine-induced relaxation of contractions Concentration-effect curves (2nM-60mM) were compared with ascorbate 200mM, Indomethacin 2.8mM, titanserin 1mM and prazosin 1 Made in the presence of mM.
４５−６０分間洗浄した後、試験化合物または５−ＨＴ （時間適合対照として ）に対する累積濃度−作用曲線を、アスコルビン酸塩、インドメタシン、コカイ ン、チタンセリンおよびプラゾシンの存在下で作成した。After washing for 45-60 minutes, test compound or 5-HT (as a time-matched control) ) for ascorbate, indomethacin, and coccyx. prepared in the presence of titanserin, titanserine, and prazosin.
５−ＨＴｔ−レセプタースクリーン ラットの尾部動脈（カラマン・エイ・ジェイおよびフレンテン・エム（Ｋａｕｍ ａｎｎ Ａ、 Ｊ、 ＆Ｆｒｅｎｋｅｎ Ｍ、 ） １９８８ 、ジャーナル・ オン・ファーマコロジー・アンド・エクスペリメンタル・セラビューティックス （Ｊ、 Ｐｈａｒｍａｃｏｌ、 Ｅｘｐ、 Ｔｈｅｒ、 ）ス土旦、１０１０− １０１５）。5-HTt-receptor screen Rat caudal artery (Karaman A.J. and Frenten M. Ann A, J, & Frenken M, ) 1988, Journal On Pharmacology and Experimental Therapeutics (J, Pharmacol, Exp, Ther,) Sutudan, 1010- 1015).
レセルピン７ｍｇ／ｋｇ ｉｐ （２０時間）で予備処理したラットの側尾部動 脈を用いた。５個の相互に連結した動脈環を調製し、修飾クレブス溶液中、３２ ゜５℃にて以下のように設置して収縮させた。環の静止力が４ｍＮであるように 膜用曲線を測定した。第１は５−ＨＴに対するものでその後洗浄し、第２は試験 化合物に対するもので、第３は使用した最高濃度の試験化合物の存在下における ５−ＨＴに対するものである。試験化合物の内在的活性を、最大の５−ＨＴ誘発 の効果に対する試験化合物誘発の効果の最大の割合として算定した。試験化合物 のＥＣ，。を対応する濃度−作用曲線より評価した。平衡解離定数Ｋｐを、マラ ノおよびカラマン法（Ｍａｒａｎｏ＆Ｋａｕｍａｎｎ）より評価した（１９７６ ． ジャーナル・オン・ファーマコロジー・アンド・エクスペリメンタル・セラ ビューティックス（Ｊ、 Ｐｈａｒｍａｃｏｌ、 Ｅｘｐ、 Ｔｈｅｒ、 ） １９旦、５１８−５２５）。Lateral caudal movements of rats pretreated with reserpine 7 mg/kg ip (20 hours) I used the pulse. Five interconnected arterial rings were prepared and incubated in modified Krebs solution for 32 min. It was placed and shrunk at 5°C as follows. As the static force of the ring is 4 mN A membrane curve was measured. The first is for 5-HT and then washed, the second is for testing for the compound, the third in the presence of the highest concentration of test compound used. 5-HT. The intrinsic activity of the test compound was determined by maximal 5-HT induction. It was calculated as the maximum ratio of the test compound-induced effect to the effect of . test compound EC,. were evaluated from the corresponding concentration-effect curves. The equilibrium dissociation constant Kp is (1976) ．． Journal on Pharmacology and Experimental Sera Beautix (J, Pharmacol, Exp, Ther,) 19th, 518-525).
式（Ｉ）の化合物は、このスクリーン法にて活性であることが証明され、例えば 、７−ヒドロキシ−８−メチルスルホニル−２，３，４，５−テトラヒドロ−Ｉ Ｈ−ベンズアゼピンは領２μＭのＥＣ，。を有し、実施例２の化合物は１μＭの ＥＣ，を有することが判明した。Compounds of formula (I) have been shown to be active in this screen method, e.g. , 7-hydroxy-8-methylsulfonyl-2,3,4,5-tetrahydro-I H-benzazepine has an EC of 2 μM. and the compound of Example 2 has 1 μM EC.
門脈圧冗進症−ｉｎ ｖｉｖ。Portal hypertension-inviv.
７−ヒドロキシ−８−メチルスルホニル−２，３，４，５−テトラヒドロ−ＩＨ −ベンズアゼピンの効果を、意識のある正常なかつ門脈系静脈を結紮したラット （スブラギューダウレイ系（Ｓｐｒａｇｕｅ−Ｄａｗｌｅｙ） ）の上編間膜動 脈流について検討した。門脈系静脈−結紮ラットにて門脈圧冗進症が記載されて いるように形成された（グロズマン（Ｇｒｏｓｚｍａｎｎ）ら、１９８２）。長 期的研究に備えて、ドツプラー（Ｄｏｐｐｌｅｒ）フローメーター消息子を上編 間膜動脈に差し込んだ。上編間膜流の変化を４日間観察し、つづいて４日間、飲 料水中、７−ヒドロキシ−８−メチルスルホニル−２，３，４，５−テトラヒド ロ−ＩＨ−ベンズアゼピンに暴露し、さらに４日間、飲料水中、７−ヒドロキシ −８−メチルスルホニル−２，３゜４．５−テ）ラヒドローＩＨ−ペンズアゼピ ン不含にて暴露した。疑似操作した（Ｓｈａｍｏｐｅｒａｔｅｄ）および門脈系 静脈結紮の両方のラットにて、７−ヒドロキシ−８−メチルスルホニル−２，３ ，４，５−テトラヒドロ−ＩＨ−ベンズアゼピンは有意に上編間膜流を減少させ た。該効果は、飲料水中、７−ヒドロキシ−８−メチルスルホニル−２，３，４ ，５−テトラヒドロ−ＩＨ−ベンズアゼピンのない最１麦の４日間で可逆的であ った。7-hydroxy-8-methylsulfonyl-2,3,4,5-tetrahydro-IH - The effects of benzazepines were investigated in conscious, normal rats with portal vein ligation. (Sprague-Dawley system) Membrane movement between upper knits We investigated pulsating flow. Portal hypertension has been described in portal vein-ligated rats. (Groszmann et al., 1982). long In preparation for periodic research, a Doppler flow meter was installed. inserted into the mesenteric artery. Changes in the upper interstitial membrane flow were observed for 4 days, followed by 4 days of drinking water. 7-hydroxy-8-methylsulfonyl-2,3,4,5-tetrahydride in water After exposure to rho-IH-benzazepine and for an additional 4 days, 7-hydroxy -8-methylsulfonyl-2,3゜4.5-te)rahydroIH-penzazepi Exposure was made without containing Shamoperated and portal venous systems In both rats with vein ligation, 7-hydroxy-8-methylsulfonyl-2,3 , 4,5-tetrahydro-IH-benzazepine significantly reduced epistitial membrane flow. Ta. This effect is due to the presence of 7-hydroxy-8-methylsulfonyl-2,3,4 in drinking water. , 5-tetrahydro-IH-benzazepine-free reversible in 4 days It was.
グロズマン・アール・ジエイ、ポロビオラフ・ジエイおよびリレイ・イー（Ｇｒ ｏｓｚｍａｎｎ ＲＪ、 Ｖｏｒｏｂｉｏｆｆ ＪおよびＲ１１ｅｙ Ｅ） （ １９８２） 。門脈圧冗進症ラットの内臓血行力学（ｓｐｌａｃｈｎｉｃ ｈｅ ｍｏｄｙｎａｍｉｃｓ ｉｎ ｐｏｒｔａｌ ｈｙｐｅｒｔｅｎｓｉｖｅ ｒａ ｔｓ）、ガンマ−標識のミクロスフェアを用いる測定。アメリカン・ジャーナル ・オン・フィジオロジ−（＾ｍ Ｊ Ｐｈｙｓｉｏｌ） ２４２ ：Ｇ１５６− Ｇｌ６０゜医薬処方 １、静脈内注入用処方 式（Ｉ ） （’）化合物０．１ １５０ｍｇ水酸化ナトリウム／塩酸 ｐＨ約 ７に調整ポリエチレングリコール Ｏ−０−３Ｏプロピレングリコール ０−０ −３Ｏ アルコール Ｏ−０−１Ｏ 水 １００ｍ１に調整 ２、ポーラス注射用処方 式（１）の化合物 ０．１−１５０ｍｇ水酸化ナトリウムまたは塩酸 ｐＨ約７ に調整ポリエチレングリコール Ｏ−２，５ｍｌアルコール ０−２．５ｍｌ 水 ５ｍｌに調整 さらに毒性調整剤、例えば塩化ナトリウム、デキストロースまたはマンニトール を加えてもよい。Grozman R.G., Poloviolav.G. and Liley Yi (Gr. oszmann RJ, Vorobioff J and R11ey E) ( 1982). Visceral hemodynamics in rats with portal hypertension modinamics in portal hypertensive ra ts), measurements using gamma-labeled microspheres. american journal ・On Physiology (^m J Physiol) 242: G156- Gl60゜Medicinal prescription 1. Prescription for intravenous injection Formula (I) (') Compound 0.1 150mg Sodium hydroxide/hydrochloric acid pH approx. Adjusted to 7 Polyethylene glycol O-0-3O Propylene glycol 0-0 -3O Alcohol O-0-1O Water adjusted to 100ml 2. Porous injection formulation Compound of formula (1) 0.1-150mg Sodium hydroxide or hydrochloric acid pH approximately 7 Polyethylene glycol O-2.5ml Alcohol 0-2.5ml Water adjusted to 5ml Additionally, toxicity modifiers such as sodium chloride, dextrose or mannitol may be added.
３、経口投与用錠剤 ｍｇ／錠剤 式（Ｉ）の化合物 ５０ ラカトース １５３ 澱粉 ３３ クロスポビドン １２ 微結晶セルロース ３０ 実施例 本発明の範囲内の化合物（例えば、７−ヒドロキシ−８−メチルスルホニル−２ 、３，４，５−テトラヒドロ−ＩＨ−３−ベンズアゼピン）は、ＥＰ−２２９５ １０−Ｂに記載の方法または以下に開示されている方法を用いて製造できる。3. Tablets for oral administration mg/tablet Compound of formula (I) 50 Lakatos 153 Starch 33 Crospovidone 12 Microcrystalline cellulose 30 Example Compounds within the scope of the invention (e.g. 7-hydroxy-8-methylsulfonyl-2 , 3,4,5-tetrahydro-IH-3-benzazepine) is EP-2295 10-B or the method disclosed below.
実施例１ ７−メドキシー８−メチルスルフィニル−、３，４，５−テトラヒドロ−ＩＨ− ベンズアゼピン・−シュウ酸塩 ３−アセチル−７−メドキシー８−メチルチオ−２，３，４，５−テトラヒドロ −ＩＨ−ベンズアゼピン（３，０４ｇ）をメタノール（５００ｍｌ）に溶かし、 室温で１０分間にわたって撹拌しながら、三塩化チタンの１５％溶液（１１，８ ｇＬつづいて６％過酸化水素溶液（１８，０ｇ）で滴下処理した。さらに３０分 間撹拌した後、反応混合物を濾過し、水で希釈してクロロホルムで抽出した。Example 1 7-medoxy8-methylsulfinyl-,3,4,5-tetrahydro-IH- Benzazepine-oxalate 3-acetyl-7-medoxy8-methylthio-2,3,4,5-tetrahydro -IH-benzazepine (3.04 g) was dissolved in methanol (500 ml), A 15% solution of titanium trichloride (11,8 Subsequently, a 6% hydrogen peroxide solution (18.0 g) was added dropwise. Another 30 minutes After stirring for a while, the reaction mixture was filtered, diluted with water and extracted with chloroform.
その抽出液を亜硫酸ナトリウム水溶液で、ついで水で洗浄し、乾燥させ、濾過し 、蒸発乾固させて固体の３−アセチル−７−メドキシー８−メチルスルフィニル −１３、４，５−テトラヒドロ−ＩＨ−ベンズアゼピン（３，２１ｇ）を得た。The extract was washed with aqueous sodium sulfite solution, then with water, dried, and filtered. , evaporated to dryness to give a solid 3-acetyl-7-medoxy-8-methylsulfinyl -13,4,5-tetrahydro-IH-benzazepine (3.21 g) was obtained.
融点１３０−２℃。Melting point: 130-2°C.
前記生成物（２０ｍｇ）を４０％水酸化ナトリウム水溶液（１ｍｌ）と−緒にイ ソプロパツール（１ｍｌ）の溶液を６０分間還流することにより加水分解した。The above product (20 mg) was mixed with 40% aqueous sodium hydroxide solution (1 ml). A solution of sopropatol (1 ml) was hydrolyzed by refluxing for 60 minutes.
大部分のイソプロパツールを真空下で蒸発させ、残りの溶液を水で希釈し、クロ ロホルムで抽出した。抽出液を合し、乾燥（ＭｇＳＣＬ）させ、蒸発させて７− メドキシー８−メチルスルフィニル−、３，４，５−テトラヒドロ−ＩＨ−ベン ズアゼピン（１７ｍｇ）を得、それを−シュウ酸塩に変えた。融点２１２−４℃ 。Evaporate most of the isopropanol under vacuum, dilute the remaining solution with water and chlorine. Extracted with loform. The extracts were combined, dried (MgSCL) and evaporated to give 7- Medoxy 8-methylsulfinyl-,3,4,5-tetrahydro-IH-ben Zuazepine (17 mg) was obtained and converted to the -oxalate salt. Melting point 212-4℃ .
実施例２ ７−メドキシー８−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩 濃硝酸（０，６ｍｌ、７０％ｗ／ｗ）を、無水酢酸（３０ｍｌ）中、３−アセチ ル−７−メドキシー２．３．４．５−テトラヒドロ−ＩＨ−ベンズアゼピン（１ ９８ｇ）の撹拌水冷溶液に５〜６時間にわたって添加した。溶液を室温にまで加 温し、−夜装置した後、炭酸水素ナトリウム飽和水溶液に加えた。過剰量の無水 酢酸をすべて反応させた場合に、得られた混合物を塩化ナトリウムで飽和させ、 酢酸エチルで抽出した。合した抽出液を水で洗浄し、乾燥（ＭｇＳＯ＜）させ、 ガム状にまで蒸発させ、それをクロマトグラフィー（ＳｉＯｚ： ＣｓＨ＋４／ ＥｔＯＡｃ）により精製し、３−アセチル−７−メドキシー８−ニトロ−２，３ ，４，５−テトラヒドロ−Ｎ（−ベンズアゼピン（０，９３ｇ）、融点１２７− １３２℃、およびベンゼンから再結晶して３−アセチル−６−ニドローフ−メト キシー２．３．４゜５−テトラヒドロ−ＩＨ−ベンズアゼピン（０，１６ｇ）、 融点１４３−１４９℃を得た。Example 2 7-medoxy8-nitro-2,3,4,5-tetrahydro-IH-benzaze pin hydrochloride Concentrated nitric acid (0.6 ml, 70% w/w) was dissolved in 3-acetyl anhydride (30 ml). Ru-7-medoxy2.3.4.5-tetrahydro-IH-benzazepine (1 98g) over a period of 5-6 hours. Warm the solution to room temperature. After warming and incubating overnight, it was added to a saturated aqueous solution of sodium bicarbonate. Excess amount of anhydrous When all the acetic acid has reacted, the resulting mixture is saturated with sodium chloride, Extracted with ethyl acetate. The combined extracts were washed with water, dried (MgSO<), It is evaporated to a gum-like state and subjected to chromatography (SiOz: CsH+4/ 3-acetyl-7-medoxy-8-nitro-2,3 ,4,5-tetrahydro-N(-benzazepine (0,93 g), melting point 127- 132°C and recrystallized from benzene to give 3-acetyl-6-nidolph-meth. xy2.3.4゜5-tetrahydro-IH-benzazepine (0.16g), A melting point of 143-149°C was obtained.
前記の生成物（３〜アセチル−７−メドキシー８−ニトロ−２，３，４，５−テ トラヒト０−ＩＨ−ベンズアゼピン）（０，９０ｇ）を、３Ｎ ＨＣＩ （５４ ｍｌ）中、還流温度で１６時間加熱した。得られた溶液を蒸発乾固させて黄色固 体を得、それをアセトンでトリチュレートし、濾：Ａ操作により収集した。こう して得られたベージュ色固体をｐ、ｏ、上で乾燥させ、メタノールより再結晶し て７−メドキシー８−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズア ゼピン・塩酸塩（０，７４ｇ）を得た。融点２３４−７℃。The above product (3-acetyl-7-medoxy-8-nitro-2,3,4,5-te 0-IH-benzazepine) (0.90g) was added to 3N HCI (54g). ml) at reflux temperature for 16 hours. The resulting solution was evaporated to dryness to a yellow solid. The product was triturated with acetone and collected by filtration:A procedure. like this The beige solid obtained was dried over P,O, and recrystallized from methanol. 7-medoxy8-nitro-2,3,4,5-tetrahydro-IH-benza Zepine hydrochloride (0.74 g) was obtained. Melting point 234-7°C.
実施例３ ７−ヒドロキシ−８−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズア ゼピン・塩酸塩 ７−メドキシー８−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩（０，４０ｇ）を臭化水素酸４８％水溶液に溶がし、その溶液を２ ４時間加熱還流した。該溶液を蒸発乾固させて粗黄色固体を得、それを塩基性化 し、りＣ１７トグラフイー （ＳｉＯｚ；ＣＨＣｌ５／ＭｅＯＨ）＋、：、Ｊ： すｌ１１ａｉｌＬ、ツいテメタノール／濃塩酸より再結晶して７−ヒドロキシ− ８−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン・塩酸塩（ ０，１１ｇ）を得た。融点２５１−５℃。Example 3 7-Hydroxy-8-nitro-2,3,4,5-tetrahydro-IH-benza Zepine hydrochloride 7-medoxy8-nitro-2,3,4,5-tetrahydro-IH-benzaze Dissolve pin hydrochloride (0.40 g) in a 48% aqueous solution of hydrobromic acid, and dilute the solution with 2 The mixture was heated under reflux for 4 hours. The solution was evaporated to dryness to give a crude yellow solid, which was basified. C17 tograph (SiOz; CHCl5/MeOH) +, :, J: 7-hydroxy- 8-nitro-2,3,4,5-tetrahydro-IH-benzazepine hydrochloride ( 0.11 g) was obtained. Melting point 251-5°C.
実施例４ ７−メドキシー８−ブロモ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩 ３−アセチル−７−メドキシー２．３．４．５−テトラヒドロ−ＩＨ−ベンズア セピン（５，０ｇ）を氷酢酸（７０ｍｌ）に溶がし、７０’Ｃに加熱した。臭素 の１４０Ｍ酢酸溶液を２０−３０分間にわたって加え、得られた溶液を７０℃で さらに１時間加熱した。その溶液を一夜冷却させ、その間に多量のベージュ色結 晶が得られた。これらの結晶を濾過により収集し、塩基性化し、クロマトグラフ ィ（ＳｉＯｚ： ＣＨｚＣ１４／ＥｔＯＡＣ）により精製し、つづイテ酢酸エチ ル／エーテルより結晶化させて３−アセチル−７−メドキシー８−ブロモ−２， ３，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン（１，５５ｇＬ融点１２３− １２５℃、および３−アセチル−６−プロモーフ−メトキシー２．３．４．−５ −テトラヒドロ−ＩＨ−ベンズアゼピン、融点９９−１０１℃を得た。Example 4 7-medoxy 8-bromo-2,3,4,5-tetrahydro-IH-benzaze pin hydrochloride 3-acetyl-7-medoxy2.3.4.5-tetrahydro-IH-benza Sepin (5.0 g) was dissolved in glacial acetic acid (70 ml) and heated to 70'C. bromine of 140M acetic acid solution was added over 20-30 minutes and the resulting solution was heated at 70°C. The mixture was further heated for 1 hour. The solution was allowed to cool overnight, during which time a large beige color formed. crystal was obtained. These crystals were collected by filtration, basified, and chromatographed. (SiOz: CHzC14/EtOAC), followed by ethyl acetate. 3-acetyl-7-medoxy-8-bromo-2, 3,4,5-tetrahydro-IH-benzazepine (1,55 gL melting point 123- 125°C, and 3-acetyl-6-promorph-methoxy2.3.4. -5 -Tetrahydro-IH-benzazepine, melting point 99-101°C was obtained.
前記の生成物（３−アセチル−７−メドキシー８−ブロモ−２，３，４，５−テ トラヒドロ−ＩＨ−ベンズアゼピン）（０，３０ｇ）を３Ｍ ＨＣＩ （１６， ５ｍ１）中、還流温度で２０時間加熱した。溶液を真空下で蒸発乾固させ、アセ トンでトリチュレートして、白色固体の７−ブロモ−８−メトキシ−２，３，４ ，５−テトラヒドロ−ＩＨ−ベンズアゼピン・塩酸塩（０，２５ｇ）を得た。融 点２６８−２７２°Ｃ０ 実施例５ ７−ヒドロキシ−８−ブロモ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズア ゼピン・塩酸塩 ジクロロメタン（１２ｍり中、３−アセチル−７−メドキシー８−ブロモ−２、 ３，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン（０，５ｇ）の溶液をアセト ン／ドライアイス洛中にて冷却した。三臭化ホウ素（０，３２ｍ１）を該撹拌溶 液に一度に加え、混合物を１時間にわたって室温にまで加温した。撹拌をさらに ３０分間続けぐついで水を加えた。混合物を水とジクロロメタンの間に分配し、 水層をジクロロメタンで再び抽出した。合した抽出液を水および塩水で洗浄し、 乾燥（ＭｇＳＯ４）させ、固体にまで蒸発させ、それをクロマトグラフィー（Ｓ ｉＯ２： ＣＨＣｌ３／ＭｅＯＨ）により精製し、白色固体として３−アセチル −７−ヒトロキンー８−ブロモ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズ アゼピン（０，３７ｇ）を得た。The above product (3-acetyl-7-medoxy-8-bromo-2,3,4,5-te Torahydro-IH-benzazepine) (0.30g) was dissolved in 3M HCI (16, 5 ml) at reflux temperature for 20 hours. The solution was evaporated to dryness under vacuum and the acetate Trituration of 7-bromo-8-methoxy-2,3,4 as a white solid , 5-tetrahydro-IH-benzazepine hydrochloride (0.25 g) was obtained. Melt Point 268-272°C0 Example 5 7-hydroxy-8-bromo-2,3,4,5-tetrahydro-IH-benza Zepine hydrochloride Dichloromethane (in 12ml, 3-acetyl-7-medoxy-8-bromo-2, A solution of 3,4,5-tetrahydro-IH-benzazepine (0.5 g) was dissolved in acetate. The mixture was cooled in a tank/dry ice container. Boron tribromide (0.32ml) was added to the stirring solution. solution in one portion and the mixture was allowed to warm to room temperature over 1 hour. More stirring Water was added continuously for 30 minutes. Partition the mixture between water and dichloromethane, The aqueous layer was extracted again with dichloromethane. The combined extracts were washed with water and brine; Dry (MgSO4) and evaporate to a solid, which is chromatographed (S iO2:CHCl3/MeOH) to produce 3-acetyl as a white solid. -7-hytroquine-8-bromo-2,3,4,5-tetrahydro-IH-benz Azepine (0.37 g) was obtained.
前記の生成物（０，３０ｇ）を３Ｎ ＨＣＩ （５０ｍｌ）中で加熱して一夜還 流した。得られた溶液を蒸発乾固させ、アセトンでトリチュレートして白色固体 を得た。これをｎ−プロパツール／ＨＣＩより再結晶し、白色結晶の標記化合物 （０，２１ｇ）を得た。融点２７７−２８１℃。The above product (0.30 g) was heated under reflux in 3N HCI (50 ml) overnight. It flowed. The resulting solution was evaporated to dryness and triturated with acetone to give a white solid. I got it. This was recrystallized from n-propanol/HCI to give the title compound as white crystals. (0.21 g) was obtained. Melting point 277-281°C.
実施例６ ツーメトキシ−６−ニトロ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩 ３−アセチル−７−メトキシ−６〜ニトロ−２，３，４，５−テトラヒドロ−Ｉ Ｈ−ベンズアゼピン・塩酸塩（０，１５ｇ）を、３Ｎ ＨＣＩ （９ｍｌ） 中 、還流温度で加熱することにより、実施例２に記載の操作に従って標記化合物を 製造した。生成物、７−メドキシー６−ニトロー２．３．４．５−テトラヒドロ −ＩＨ−ベンズアゼピン・塩酸塩を記載どおりに単離し、ｎ−プロパツールから 再結晶し、小片黄色結晶（０，０７７ｇ）を得た。融点２５８−６１℃分解。Example 6 Twomethoxy-6-nitro-2,3,4,5-tetrahydro-IH-benzaze pin hydrochloride 3-acetyl-7-methoxy-6-nitro-2,3,4,5-tetrahydro-I H-benzazepine hydrochloride (0.15g) in 3N HCI (9ml) , the title compound was prepared according to the procedure described in Example 2 by heating at reflux temperature. Manufactured. Product, 7-medoxy6-nitro 2.3.4.5-tetrahydro -IH-benzazepine hydrochloride was isolated as described and from n-propatool. Recrystallization gave small pieces of yellow crystals (0,077 g). Melting point 258-61°C decomposed.
実施例７ ローブロモー７−メトキシー２．３．４．５−テトラヒドロ−ＩＨ−ベンズアゼ ピン・塩酸塩 ３−アセチル−６−プロモーフ−メトキシー２．３．４．５−テトラヒドロ−Ｉ Ｈ−ベンズアゼピン（０，２０ｇ）を、３Ｎ ＨＣＩ （１１ｍ’ｌ） 中、還 流部［Ｔ加熱することにより、実施例２に記載の操作に従って標記化合物を製造 した。生成物、６−プロモーフ−メトキシー２．３．４．５−テ篩ヒドローＩＨ −ベンズアゼピン・塩酸塩を記載どおりに単離し、ｎ−プロパツールから再結晶 し、白色針状晶（０，，１２ｇ）を得り。Ｍ点２５５−６０℃。Example 7 Lobromo 7-methoxy2.3.4.5-tetrahydro-IH-benzaze pin hydrochloride 3-acetyl-6-promorph-methoxy2.3.4.5-tetrahydro-I H-benzazepine (0.20 g) was refluxed in 3N HCI (11 ml). The title compound was prepared according to the procedure described in Example 2 by heating the stream [T] did. Product, 6-Promorph-Methoxy2.3.4.5-Tesieve Hydro IH - Benzazepine hydrochloride was isolated as described and recrystallized from n-propanol. Then, white needle crystals (0.12g) were obtained. M point 255-60°C.
実施例８ ８−アセチル−７−ヒドロキシ−２，３，４，５−テトラヒドロ−ＩＨ−ベンズ アゼピン・塩酸塩 四塩化スズ（２，４ｍ１）を、室温で、ＣＨｚＣｌｔ （１５ｍｌ）中、塩化ア セチル（１，４６ｍ１）の溶液に撹拌しながら滴下した。撹拌をさらに１時間続 け、ライでＣＨｚＣｌ、（１５ｍｌ）中、７−メドキシー３−アセチル−２，３ ，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン・塩酸塩（３，０ｇ）の溶液を ２０分間にわたって加えた。該混合物を放置して１６時間撹拌し、ついで３Ｎ ＨＣＩとＣＨｘ Ｃ１ｍの間に分配した。水層を再び抽出し、合した有機層を炭 酸水素ナトリウム飽和溶液で、ついでＨ２Ｏで洗浄し、乾燥（ＭｇＳＯ４）させ て蒸発させた。Example 8 8-acetyl-7-hydroxy-2,3,4,5-tetrahydro-IH-benz Azepine/hydrochloride Tin tetrachloride (2.4 ml) was added to chloride in CHzClt (15 ml) at room temperature. It was added dropwise to a solution of cetyl (1.46 ml) with stirring. Continue stirring for another hour. 7-medoxy-3-acetyl-2,3 in CHzCl, (15 ml) , 4,5-tetrahydro-IH-benzazepine hydrochloride (3.0 g) solution Added over 20 minutes. The mixture was left to stir for 16 hours, then 3N It was distributed between HCI and CHx C1m. Extract the aqueous layer again and combine the organic layers with charcoal. Washed with saturated sodium hydroxide solution, then with H2O and dried (MgSO4). and evaporated.
残渣をメタノールに溶かし、チャコール処理した。濾液を蒸発乾固させ、残渣を 沸騰ベンゼンで２回抽出し、デカントした抽出液を合し、蒸発させて固体を得、 それをエーテルでトリチュレートした。生成物、３．８−ジアセチル−７−メド キシー２．３．４．５−テトラヒドロ−ＩＨ−ベンズアゼピン（１，７ｇ）を灰 白色固体として得た。融点１４２−６℃。The residue was dissolved in methanol and treated with charcoal. The filtrate was evaporated to dryness and the residue Extracted twice with boiling benzene, combined the decanted extracts and evaporated to obtain a solid, Triturated it with ether. Product, 3,8-diacetyl-7-med xy2.3.4.5-tetrahydro-IH-benzazepine (1.7 g) Obtained as a white solid. Melting point 142-6°C.
該３．８−ジアセチルー７−メドキシー２．３．４．５−テトラヒドロ−ＩＨ− ベンズアゼピン（０，２０ｇ）をＣＨ２Ｃｌ２（５ｍｌ）に溶かし、約−７０℃ （アセトン／固体ＣＯ２浴）に冷却した。三塩化ホウ素（１，０ＭのＣＨ＊ Ｃ １を溶液；１．５３ｍ１）をシリンジで１０分間にわたって加えた。混合物を室 温までゆっくりと加温しく１時間）、ついでさらに３０分間撹拌した。ＨｉＯを 添加することで反応物をクエンチし、該混合物を水とＣＨＩＣ１２の間に分配し た。水層をジクロロメタンで再び抽出し、合した有機層を水および塩水で洗浄し 、乾燥（ＭｇＳ０４）させた。蒸発に付してガム状物を得、それをフラツシュク ロマトグラフイー（ＳｊＯ，； ＣＨＣｌ３／ＭｅＯＨ）により精製した。生成 物、３．８−ジアセチル−７−ヒドロキシ−２，３，４，５−テトラヒドロ−Ｉ Ｈ−ベンズアゼピンを、灰白色固体として、エーテルより結晶化させた（０．１ ２９ｇ）。融点１３１−４℃。The 3.8-diacetyl-7-medoxy2.3.4.5-tetrahydro-IH- Dissolve benzazepine (0.20 g) in CH2Cl2 (5 ml) and heat at approximately -70°C. (acetone/solid CO2 bath). Boron trichloride (1,0M CH*C 1 solution; 1.53 ml) was added via syringe over 10 minutes. chamber the mixture The mixture was slowly warmed to warm temperature for 1 hour) and then stirred for an additional 30 minutes. HiO Quench the reaction by adding and partition the mixture between water and CHIC12. Ta. The aqueous layer was extracted again with dichloromethane and the combined organic layers were washed with water and brine. , dried (MgS04). Evaporate to obtain a gum-like product, which is then crushed Purified by chromatography (SjO, CHCl3/MeOH). Generate 3,8-Diacetyl-7-hydroxy-2,3,4,5-tetrahydro-I H-benzazepine was crystallized from ether as an off-white solid (0.1 29g). Melting point 131-4°C.
前記のジアセチル化合物（０，１２１ｇ）を、３Ｍ ＨＣＩ （３，７ｍ１）中 、還流温度で１６時間加熱した。ついて、該溶液を蒸発乾固させて黄橙色の結晶 固体を得た。該固体をＨＣＩ気体が溶解して含まれているｎ−プロ／くノールよ り再結晶し、小片樗色結晶として、生成物、８−アセチル−７−ヒドロキシ−２ ，３，４゜５−テトラヒドロ−ＩＨ−ベンズアゼピン・塩酸塩（０，０６４ｇ） を得た。融点２４１−７℃分解。The above diacetyl compound (0,121 g) was added in 3M HCI (3,7 ml). , and heated at reflux temperature for 16 hours. Then, the solution was evaporated to dryness to give yellow-orange crystals. A solid was obtained. The solid was dissolved in n-pro/cnol containing dissolved HCI gas. The product, 8-acetyl-7-hydroxy-2, was recrystallized as small pieces of orange crystals. ,3,4゜5-tetrahydro-IH-benzazepine hydrochloride (0,064g) I got it. Melting point 241-7°C decomposition.
実施例９ ７−ヒドロキシ−８−メチルスルフィニル−２，３，４，５−テトラヒドロ−Ｉ Ｈ−ベンズアゼピン 塩化アルミニウム（１，７１ｇ）を室温でジクロロメタンに加え、ジクロロメタ ン中、３−アセチル−７−メドキシー８−メチルスルフィニル−２，３，４，５ −テトラヒドロ−ＩＨ−ベンズアゼピン（０，９０ｇ）の溶液を３時間にわたっ て撹拌しながら滴下した。該混合物を放置して一夜撹拌させた後、該ジクロロメ タン溶液を沈殿ガム状物よりデカントした。その物質を水酸化ナトリウム１Ｍ溶 液で温浸させ、得られた水溶液をジクロロメタンで洗浄し、濃ＨＣ１でｐＨ２に 酸性化し、クロロホルムで抽出（３Ｘ）した。抽出液を乾燥（ＭｇＳＯ４）させ 、油にまで蒸発させ、クロマトグラフィー（Ｓｉｎｓ；ＭｅＯＨ／ＣＨｚＣ１ｔ ）により精製し、３−アセチル−７−ヒドロキシ−８−メチルスルフィニル−２ ，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン（０，７２ｇ）を得た。Example 9 7-hydroxy-8-methylsulfinyl-2,3,4,5-tetrahydro-I H-benzazepine Add aluminum chloride (1.71 g) to dichloromethane at room temperature, 3-acetyl-7-medoxy-8-methylsulfinyl-2,3,4,5 A solution of -tetrahydro-IH-benzazepine (0.90 g) was added over a period of 3 hours. The mixture was added dropwise while stirring. After the mixture was allowed to stir overnight, the dichloromethane The tongue solution was decanted from the precipitated gum. Dissolve the substance in 1M sodium hydroxide. The resulting aqueous solution was washed with dichloromethane and brought to pH 2 with concentrated HCl. Acidified and extracted with chloroform (3X). Dry the extract (MgSO4) , evaporated to an oil and chromatographed (Sins; MeOH/CHzClt ), 3-acetyl-7-hydroxy-8-methylsulfinyl-2 , 3,4,5-tetrahydro-IH-benzazepine (0.72 g) was obtained.
前記の生成物（０，６４ｇ）を水酸化ナトリウム１Ｍ溶液（１０ｍｌ）と−緒に １００℃で一夜加熱した。冷却後、混合物をイオン交換カラム（アンバーライト （＾ｍｂｅｒｌｉｔｅ） ＣＧ５０ ； ＮＨ４つに通して水で溶出した。得ら れた溶出液を蒸発乾固させ、熱メタノールで抽出し、活性チャコールで処理し、 濾過し、緑色ガム状に蒸発させた。アセトニトリルを加えて該物質を結晶化させ 、標記化合物（０，４５ｇ）を得た。融点１７５−８℃。The above product (0.64 g) was mixed with 1M sodium hydroxide solution (10 ml). Heated at 100°C overnight. After cooling, the mixture was transferred to an ion exchange column (Amberlite (^mberlite) CG50; Passed through 4 NHs and eluted with water. Obtained The eluate was evaporated to dryness, extracted with hot methanol, treated with activated charcoal, Filtered and evaporated to a green gum. Add acetonitrile to crystallize the substance , the title compound (0.45 g) was obtained. Melting point 175-8°C.
実施例１０ ７−ヒドロキシ−８−トリフルオロメチルスルホニル−２，３，４，５−テトラ ヒドロ−ＩＨ−ベンズアゼピン ３−アセチル−７−メドキンー２．３゜４．５−テトラヒドロ−ＩＨ−ベンズア ゼピン（７，０ｇ）を乾燥ジクロロメタン（１００ｍｌ）に溶かし、水浴中で冷 却し、撹拌しながらクロロスルホン酸（１３，９ｇ）で滴下処理した。該混合物 を室温でさらに２．５時間撹拌し、ついで注意して水上に注いだ。得られた褐電 油をジクロロメタンと水の間に分配し、水層をさらにジクロロメタンで抽出した 。Example 10 7-hydroxy-8-trifluoromethylsulfonyl-2,3,4,5-tetra Hydro-IH-benzazepine 3-acetyl-7-medquin-2.3゜4.5-tetrahydro-IH-benza Zepine (7.0 g) was dissolved in dry dichloromethane (100 ml) and cooled in a water bath. The mixture was cooled and treated dropwise with chlorosulfonic acid (13.9 g) while stirring. the mixture The mixture was stirred at room temperature for an additional 2.5 hours and then carefully poured onto water. Obtained brown electricity The oil was partitioned between dichloromethane and water and the aqueous layer was further extracted with dichloromethane. .
合した有機抽出液を乾燥（ＭｇＳＯ４）させ、蒸発させて３−アセチル−７−メ ドキンー８−クロロスルホニル−２，３，４，５−テトラヒドロ−ＩＨ−ベンズ アゼピン（４，５ｇ）を得た。The combined organic extracts were dried (MgSO4) and evaporated to 3-acetyl-7-methane. Doquin-8-chlorosulfonyl-2,3,4,5-tetrahydro-IH-benz Azepine (4.5 g) was obtained.
前記の生成物（３，９５ｇ）を酢酸（７５ｍｌ）に溶かし、塩化第一錫・三水和 物（１１，２ｇ）および濃ＨＣＩ（１５ｍｌ）を加えた。混合物を７５℃で１時 間撹拌し、ついで氷水中に注ぎ、酢酸エチルと一緒に振盪した。こうして得られ た固体を酢酸エチル抽出液と一緒に合し、真空下で蒸発乾固させた。この粗生成 物を乾燥エタノール（２００ｍｌ）と−緒に振盪して濾過した。得られた固体を ＩＭＮａＯＨ溶ｉｆｆｌ（１００ｍｌ）と共に３０分間撹拌し、濾過し、濃ＨＣ Ｉで酸性化し、クロロホルムで抽出した。抽出液を合し、乾燥（ＭｇＳＯ＜）さ せ、蒸発乾固させて３−アセチル−７−メドキシー８−メルカプト−２，３，４ ，５−テトラヒドロ−１１１−ベンズアゼピン（１，８６ｇ）を得た。The above product (3.95 g) was dissolved in acetic acid (75 ml) and stannous chloride trihydrate was added. (11.2 g) and concentrated HCI (15 ml) were added. Heat the mixture at 75°C for 1 hour. The mixture was stirred for a while, then poured into ice water and shaken with ethyl acetate. obtained in this way The solids were combined with the ethyl acetate extracts and evaporated to dryness under vacuum. This crude production The material was shaken with dry ethanol (200ml) and filtered. The obtained solid Stir for 30 min with IMNaOH solution (100 ml), filter, and add concentrated H.C. Acidified with I and extracted with chloroform. Combine the extracts and dry (MgSO<). and evaporated to dryness to give 3-acetyl-7-medoxy-8-mercapto-2,3,4 , 5-tetrahydro-111-benzazepine (1.86 g) was obtained.
この生成物（１，２２ｇ）を乾燥ＤＭＦ （５０ｍｌ）に溶かし、炭酸カリウム （１，３３ｇ）を加えた。５時間、Ｕ、Ｖ光を照射させ、冷却しながら、ヨウ化 トリフルオロメチルを該溶液中に通気した。真空下で大部分のＤＭＦを除去し、 残渣をクロロホルムとＩＪｉＮａＯＨ溶液の間に分配した。その有機相を乾燥（ ＭｇＳＯ４）させて蒸発乾固させた。残渣をクロマトグラフィー（Ｓｉｎ、；Ｃ １−ｌＣｌ＋／’ＭｅＯＨ）に付して精製し、３−アセチル−７−メドキシー８ −トリフルオロメチル−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン （０，３３ｇ）を得た。This product (1.22 g) was dissolved in dry DMF (50 ml) and potassium carbonate was added. (1.33 g) was added. Iodide by irradiating with U and V light for 5 hours and cooling. Trifluoromethyl was bubbled into the solution. Remove most of the DMF under vacuum, The residue was partitioned between chloroform and IJiNaOH solution. Dry the organic phase ( MgSO4) and evaporated to dryness. The residue was chromatographed (Sin, ;C 1-1Cl+/'MeOH) and purified with 3-acetyl-7-medoxy8 -trifluoromethyl-2,3,4,5-tetrahydro-IH-benzazepine (0.33g) was obtained.
前記生成物（１，０ｇ）を１．２−ジクロロエタン（７５ｍｌ）に溶かし、メタ ークロロ過安慝香酸（２，２６ｇ）を加えた。混合物を還流温度で２時間加熱し た。得られた冷却溶液を１ＭＮａＯＨ溶液て洗浄し、乾燥（Ｍｇ Ｓ Ｏ４）さ せ、蒸発乾固させて３−アセチル−７−メドキシー８−トリフルオロメチルスル ホニル−２，３，４，５−テトラヒドロ−ＩＨ−ベンズアゼピン（０，９５ｇ） を得た。The above product (1.0 g) was dissolved in 1,2-dichloroethane (75 ml) and dissolved in methane. -Chloroperbenzoic acid (2.26 g) was added. The mixture was heated at reflux temperature for 2 hours. Ta. The resulting cooled solution was washed with 1M NaOH solution and dried (MgSO4). and evaporated to dryness to give 3-acetyl-7-medoxy-8-trifluoromethylsulfate. Honyl-2,3,4,5-tetrahydro-IH-benzazepine (0,95g) I got it.
この生成物（０，５０ｇ）をジクロロメタン（１００ｍｌ）に溶かし、三臭化ホ ウ素（０，７１ｇ）を室温で一夜撹拌しながら滴下した。メタノールを注意して 滴下し、真空下で溶媒を除去した。７−ヒドロキシ化合物からなる残りの緑色部 をクロロホルムに溶かし、１ＭＮａＯＨ溶液で洗浄した。Dissolve this product (0.50 g) in dichloromethane (100 ml) and Uron (0.71 g) was added dropwise with stirring at room temperature overnight. Be careful with methanol was added dropwise and the solvent was removed under vacuum. The remaining green part consists of 7-hydroxy compounds was dissolved in chloroform and washed with 1M NaOH solution.
その水相を分離し、１００℃で４０時間加熱し、冷却してイオン交換カラム（ア ンバーライトＣＧ−５０（Ｈ））に通した。関連フラクションを合し、蒸発乾固 させて残渣を得、それをクロマトグラフィー（ＳｉＯｚ；ＣＨＣｌ５／ＭｅＯＨ ／ＮＨ，ＯＨ）にｆ寸して生成物を得、アセトニトリルから結晶化させて標記化 合物（０，１２ｇ）を得た。融点〉２７３℃。The aqueous phase was separated, heated at 100°C for 40 hours, cooled and CG-50 (H)). Combine relevant fractions and evaporate to dryness. to obtain a residue, which was chromatographed (SiOz; CHCl5/MeOH /NH,OH) to give the product, which was crystallized from acetonitrile with the title A compound (0.12 g) was obtained. Melting point>273°C.
国際調査報告 国際調査報告 フロントページの続き （８１）指定回 ＥＰ（ＡＴ、ＢＥ、ＣＨ，ＤＥ。international search report international search report Continuation of front page (81) Specified times EP (AT, BE, CH, DE.
ＤＫ、ＥＳ、ＦＲ，ＧＢ、ＧＲ，ＩＴ、ＬＵ、ＭＣ，ＮＬ、 ＳＥ）、 ＡＵ、 ＣＡ、ＪＰ、 ＫＲ，ＵＳ（７２）発明者 ヤング、ロドニー・クリストファ ーイギリス国ハートフォードシャー・エイエル６・９エイアール、ウェルウィン 、ザ・フリス（番地の表示なし） スミスクライン・ビーチャム・ファーマシュ ーティカルズ （７２）発明者 カウマン、アルベルト・ジュリオイギリス国ハートフォードシ ャー°エイエル６・９エイアール、ウェルウィン、ザ・フリス（番地の表示なし ） スミスクライン・ビーチャム・ファーマシューティカルズDK, ES, FR, GB, GR, IT, LU, MC, NL, SE), AU, CA, JP, KR, US (72) Inventor Young, Rodney Christopher - Welwyn, A.R. 6.9, Hertfordshire, United Kingdom , The Frith (no address displayed) SmithKline Beecham Farmash -ticals (72) Inventor Cowman, Alberto Giulio Hertfordshire, UK 6/9 A.R., Welwyn, The Frith (no address displayed) ) SmithKline Beecham Pharmaceuticals
Claims (12)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB919113379A GB9113379D0 (en) | 1991-06-21 | 1991-06-21 | Medicaments |
| GB9113379.3 | 1991-06-21 | ||
| GB919113377A GB9113377D0 (en) | 1991-06-21 | 1991-06-21 | Medicaments |
| GB9113377.7 | 1991-06-21 | ||
| PCT/GB1992/001083 WO1993000094A2 (en) | 1991-06-21 | 1992-06-17 | Use of tetrahydrobenzazepine derivatives for the treatment of portal hypertension and migraine |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH06508352A true JPH06508352A (en) | 1994-09-22 |
Family
ID=26299102
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4511087A Pending JPH06508352A (en) | 1991-06-21 | 1992-06-17 | Use of tetrahydrobenzazepine derivatives for the treatment of portal hypertension and migraine |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0589973A1 (en) |
| JP (1) | JPH06508352A (en) |
| KR (1) | KR940701258A (en) |
| AU (1) | AU1927992A (en) |
| CA (1) | CA2110575A1 (en) |
| IE (1) | IE921990A1 (en) |
| MX (1) | MX9203012A (en) |
| PT (1) | PT100602A (en) |
| WO (1) | WO1993000094A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013536859A (en) * | 2010-09-01 | 2013-09-26 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Non-hygroscopic salt of 5-HT2C agonist |
| JP2013536858A (en) * | 2010-09-01 | 2013-09-26 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Fast-dissolving dosage form of 5-HT2C agonist |
| JP2013539470A (en) * | 2010-09-01 | 2013-10-24 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Salt of lorcaserine and optically active acid |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9211277D0 (en) | 1992-05-28 | 1992-07-15 | Glaxo Group Inc | Pharmaceutical compositions |
| EP0932407A4 (en) * | 1996-03-25 | 2002-04-24 | Lilly Co Eli | Method for treating migraine pain |
| US7189753B1 (en) | 1997-11-06 | 2007-03-13 | Cady Roger K | Preemptive prophylaxis of migraine |
| WO2002074746A1 (en) * | 2001-03-16 | 2002-09-26 | Yamanouchi Pharmaceutical Co., Ltd. | Benzazepine derivatives |
| US6953787B2 (en) * | 2002-04-12 | 2005-10-11 | Arena Pharmaceuticals, Inc. | 5HT2C receptor modulators |
| ATE441417T1 (en) | 2002-12-20 | 2009-09-15 | Glaxo Group Ltd | BENZOADUAZEPINE DERIVATIVES FOR THE TREATMENT OF NEUROLOGICAL DISEASES |
| US7704993B2 (en) | 2003-06-17 | 2010-04-27 | Arena Pharmaceuticals, Inc. | Benzazepine derivatives and methods of prophylaxis or treatment of 5ht2c receptor associated diseases |
| MXPA05013364A (en) | 2003-06-17 | 2006-03-17 | Arena Pharm Inc | Benzazepine derivatives useful for the treatment of 5ht2c receptor associated diseases. |
| TW200510324A (en) * | 2003-08-11 | 2005-03-16 | Lilly Co Eli | 6-(2,2,2-trifluoroethylamino)-7-chiloro-2, 3, 4, 5-tetrahydro-1h-benzo[d]azepine as a 5-ht2c receptor agonist |
| BRPI0519726B8 (en) | 2004-12-21 | 2021-05-25 | Arena Pharm Inc | (r)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1h-3-benzazepine hemidrate compound, composition comprising said compound and its uses |
| BRPI0515862A2 (en) | 2004-12-23 | 2011-10-11 | Arena Pharm Inc | use of phentermine and 5ht-2c receptor selective agonist in the preparation of compositions, 5ht-2c receptor modulating compositions and unit dosage form comprising the same |
| JP5199997B2 (en) | 2006-04-03 | 2013-05-15 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Process for preparing 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and related intermediates |
| JP5404414B2 (en) | 2006-12-05 | 2014-01-29 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Method for preparing (R) -8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and its intermediates |
| US8822727B2 (en) | 2008-03-04 | 2014-09-02 | Arena Pharmaceuticals, Inc. | Processes for the preparation of intermediates related to the 5-HT2C agonist (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine |
| WO2010148207A2 (en) | 2009-06-18 | 2010-12-23 | Arena Pharmaceuticals, Inc. | Processes for the preparation of 5-ht2c receptor agonists |
| KR20130112848A (en) | 2010-06-02 | 2013-10-14 | 아레나 파마슈티칼스, 인크. | Processes for the preparation of 5-ht2c receptor agonists |
| EP3485878A1 (en) | 2010-09-01 | 2019-05-22 | Arena Pharmaceuticals, Inc. | Modified-release dosage forms of 5-ht2c agonists useful for weight management |
| US8999970B2 (en) | 2010-09-01 | 2015-04-07 | Arena Pharmaceuticals, Inc. | Administration of an anti-obesity compound to individuals with renal impairment |
| CA2886875A1 (en) | 2012-10-09 | 2014-04-17 | Arena Pharmaceuticals, Inc. | Method of weight management |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4659706A (en) * | 1985-12-20 | 1987-04-21 | Smithkline Beckman Corporation | Sulfinyl and sulfonyl substituted 3-benzazepines |
-
1992
- 1992-06-17 CA CA002110575A patent/CA2110575A1/en not_active Abandoned
- 1992-06-17 KR KR1019930703940A patent/KR940701258A/en not_active Withdrawn
- 1992-06-17 EP EP92912293A patent/EP0589973A1/en not_active Withdrawn
- 1992-06-17 PT PT100602A patent/PT100602A/en not_active Application Discontinuation
- 1992-06-17 JP JP4511087A patent/JPH06508352A/en active Pending
- 1992-06-17 WO PCT/GB1992/001083 patent/WO1993000094A2/en not_active Ceased
- 1992-06-17 AU AU19279/92A patent/AU1927992A/en not_active Abandoned
- 1992-06-19 MX MX9203012A patent/MX9203012A/en unknown
- 1992-07-01 IE IE199092A patent/IE921990A1/en not_active Application Discontinuation
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013536859A (en) * | 2010-09-01 | 2013-09-26 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Non-hygroscopic salt of 5-HT2C agonist |
| JP2013536858A (en) * | 2010-09-01 | 2013-09-26 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Fast-dissolving dosage form of 5-HT2C agonist |
| JP2013539470A (en) * | 2010-09-01 | 2013-10-24 | アリーナ ファーマシューティカルズ， インコーポレイテッド | Salt of lorcaserine and optically active acid |
Also Published As
| Publication number | Publication date |
|---|---|
| KR940701258A (en) | 1994-05-28 |
| WO1993000094A2 (en) | 1993-01-07 |
| CA2110575A1 (en) | 1993-01-07 |
| MX9203012A (en) | 1993-07-01 |
| IE921990A1 (en) | 1992-12-30 |
| AU1927992A (en) | 1993-01-25 |
| PT100602A (en) | 1993-09-30 |
| EP0589973A1 (en) | 1994-04-06 |
| WO1993000094A3 (en) | 1993-03-04 |
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